Mozzies knocked out with gene drive – Expert Reaction

UK researchers say they’ve successfully used a CRISPR-based gene drive to cause the collapse of a population of caged malaria-carrying mosquitoes.

The study, published today, targeted a gene that determines whether an individual mosquito develops as a male or a female. Previous attempts have been thwarted by the mosquitoes developing resistance to the gene drive, but the researchers say this didn’t happen and within eight generations no females were being produced and the population collapsed.

The SMC asked experts to comment on the study.

Joint comment – Professor Peter Dearden and Professor Neil Gemmell, University of Otago:

“The paper by Kyrou et al. is an interesting and important step forward in the development of gene drive technologies. These technologies may make possible the extinction of a population of a pest, or as here, a disease-carrying organism using genetic techniques. This paper describes a gene drive system, used in a contained lab experiment, that drives the extinction of a malaria-carrying mosquito.

“The reason this paper is a step forward is that the target gene chosen in this manuscript allows the authors to solve one of the problems with gene drives, which is the development of resistance. By targeting a gene involved in specifying the sex of mosquitos, they have ensured that when resistance arises it leads to female infertility, and is selected against.

“The gene drive has little to no effect in males, meaning that while females are sterile, the males keep spreading the gene drive mechanism, leading to more infertile females and finally population collapse.

“The gene targeted is present in most insects and acts in a similar way, indeed this similar approach has been proposed as a technology for wasp control in New Zealand.

“The authors state that they believe that such mosquitos might be available for release to the wild in 5-8 years, and that there is a lot of research and testing to be done before then. One missing aspect of this approach is a technology that allows a gene drive to be turned off or limited once released, something that needs to be investigated.

“The timeline for developing these mosquitos is a strong signal that work on gene drive systems for pests in New Zealand will take a long time without significant investment. Currently there is some disquiet about such work, and we need to continue to pursue such research in contained labs to understand the risks and benefits if we are to ever be in a position to trial such tools for the control of our pests, whether it is wasps, rats, or something new that threatens our economy or health.”

Our colleagues at the Australian SMC also gathered comments on the study.

Professor Ary Hoffmann is Director of Research at the Centre for Environmental Stress and Adaptation Research, University of Melbourne

“This is an interesting development in the potential use of gene drive systems to suppress pest populations.

In particular, the authors target the essential doublesex gene that is involved in the sex determination pathway and needed for normal development of males and females. A construct was developed that prevents females developing normally and results in them producing a sharply reduced number of viable eggs.  This construct could be driven through the population, and importantly appears to be stable so far – it has proven resistant to the rapid evolution of genetic variants that stop the gene drive acting.

Importantly, the work shows that there is a very rapid decrease in egg number in population cages such that populations of Anopheles mosquitoes eventually collapse.

It remains to be seen if the same phenomenon can be reproduced in large cages designed to represent field populations more closely where there is a greater chance of mutations arising that prevent the gene drive from operating properly.

Nevertheless, at least in the short term, the experiments show that it is possible to produce a stable drive to suppress populations of mosquito disease vectors.”

Ary has not declared any conflicts of interest. 

Dr Gordana Rasic is a senior research officer in the Mosquito Control Group, QIMR Berghofer Medical Research Institute

“In this study, scientists created a new gene drive that disrupts development of female malarial mosquitoes (Anopheles gambiae) and causes their caged populations to crash.

Andrea Crisanti’s group at Imperial College, UK has used CRISPR technology to create a mutation in a gene (doublesex) that prevents normal development of biting females but does not affect harmless male mosquitoes.

By linking the mutation to a CRISPR-based machinery that ensures it is transmitted nearly 100 per cent of the time, the mutation quickly spreads through a population, turning more and more females into intersex mosquitoes that can’t bite and reproduce.

The heavy hit on egg production was enough to cause total collapse of experimental caged populations in less than a year.

This is not the first gene drive for suppression of malarial mosquitoes that Crisanti’s group has created, but the doublesex construct seems much more resilient to mosquitoes developing resistance to it, and this is what gives hope it might work in the field.

Field trials are indeed the ultimate test for the efficacy of suppression gene drives, but the releases of such GM mosquitoes are met with heavy regulatory constraints and public skepticism.

An important breakthrough happened this August, when Burkina Faso’s national biosafety authority granted permission to release 10,000 non-gene-drive GM Anopheles mosquitoes, as a first step towards eventual rollout of the gene drive constructs like Crisanti’s.

Exciting and hopeful times in fight against malaria are ahead.”

Gordana has not declared any conflicts of interest. 

Dr Cameron Webb is a Clinical Lecturer with the University of Sydney

“Novel approaches to mosquito control are critical if we are to reduce the burden of mosquito-borne disease. Traditional approaches to controlling mosquitoes, especially the use of insecticides, is becoming less effective as key mosquitoes involved in outbreaks of disease are becoming resistant to our commonly-used insecticides.

As malaria is still responsible for killing over half a million people every year and making hundreds of millions of people sick, new technologies are required to battle mosquito-borne disease.

While gene drives have shown great potential in the past, laboratory studies have demonstrated that resistance in mosquitoes to these approaches developed in much the same way that they’re beating our commonly-used insecticides.

This new research, however, opens new potential applications of this strategy and provides support for researchers to pursue field-based studies. No such resistance to this approach was shown in these newly published laboratory studies.

By releasing laboratory-reared, genetically-modified mosquitoes into the field, they can crash the local mosquito populations by reducing the proportion of fertile female mosquitoes. It is a tantalising prospect that collapsing mosquito populations may substantially reduce the transmission of mosquito-borne pathogens.

This latest research demonstrates great potential for future management of malaria in many parts of the world, especially Africa.

However, adapting this approach to Australian mosquito-borne disease may face many challenges. Australia is free of malaria but thousands of people fall ill following mosquito bites each summer.

Unfortunately, there are many different types of mosquito, found in many different types of environments, that drive outbreaks of mosquito-borne disease here.

The release of genetically modified mosquitoes is still a long way off but perhaps in the future it will be an additional tool available to local health authorities in reducing the public health risks associated with our local mosquitoes.”

Cameron has not declared any conflicts of interest.